The normal mammalian immune system responds to the introduction of “non-self” antigens, such as antigens present on transplanted tissues, through a variety of complex mechanisms. One such mechanism is the recognition and destruction of such antigens by T lymphocytes (T cells), which selectively kill cells expressing “non-self” antigens, while leaving cells expressing only self antigens unharmed.
Antigen processing is necessary for any antigen to be recognized, and reacted to, by the immune system. For exogenous antigens, such as antigens present on transplanted tissue, processing begins with the uptake and fragmentation of the antigen by APCs. The antigen fragments associate with major histocompatability complex (MHC) proteins, specifically the class II type, and the combination “presents” on the APC surface. MHC class I proteins generally associate with antigens produced within the cell, such as viral proteins. The surface expression of two Co-simulators, CD 80 and CD 86, has also proven to be necessary for effective presentation of an antigen. T cells that express T cell receptors (TCRs) specific for the MHC/antigen complex and the receptor for CD 80/86, known as CD 28, are stimulated upon association with the APCs. The stimulation results in the production of cytokines and proliferation of T cells with that receptor specificity. The interaction between the specific T cells, the cytokines, and other components of the immune system selectively eliminate cells expressing the exogenous antigen, such as the transplanted tissue.
There are three general classes of APCs—macrophages, dendritic cells, and B cells. Dendritic cells are an important type of APC for stimulation with newly encountered antigens, and are likely to be important for rejection of transplant. Immature macrophages, or monocytes, are present in the circulating blood. Upon activation by stimulators such as interferons and bacteria (IL)-12, IL-10 and tumor neurosis factor TNF, among other immune regulators. Activation also results in the expression of MHC class I and II proteins and CD 80/86 on the cell surface. Dendritic cells are present in the skin and associated with lymphoid tissues throughout the body, and can be found in relatively low concentrations in the blood in different stages of maturation. The dendritic cells in the lymphoid tissue are found in association with T and B cell populations and are extremely effective presentors of antigens to these immune cells. Finally, B cells act as APCs through the binding of whole antigen molecules by surface antigen receptors, that are internalized and processed for presentation. Thus, processing and surface presentation by APCs can be thought of as a first step in the normal immune response.
Although immune recognition of “non-self” proteins is essential to avoid and eliminate infection, the immune response can sometimes be unwanted. Autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis or insulin dependent diabetes mellitus, are the result of a pathological immune response against self antigens, and T cells are the primary mediators of autoimmunity. Rejection of transplanted organs and tissues are a further example of an undesired consequence of normal immunity, which can often result in damage to and/or rejection of the transplant.
Efforts have been made in the past to disarm the immune system using corticosteroids (such as methylprednisilone) or, cytotoxic drugs (such as cyclophosphamide), but the widespread and non-specific effects of these treatments often limit their utility or effectiveness. More specific immune modulators, such as FK506, have fewer undesired side effects, but still inhibit the entire immune response, rather than specific immune responses or responses directed to specific tissues. However, more recent efforts have been made to target particular molecular mechanisms of immunity to further refine the ability to modulate specific responses.
An impaired cellular immune response is a characteristic of many tumors in both animal models and human patients (Fujiwara et al., 1995 and Clerici et al., 1998). This diminished cellular immunity is not necessarily limited to reactivity against tumor-specific antigens, but can include unresponsiveness to non-tumor antigens and T cell mitogens (Mahaley et al., 1977 and Gruss et al., 1997). Cytokine dysfunction appears to contribute to tumor-associated immune dysregulation, with decreases of in vitro IL-2 and/or IFN-γ production and increases in IL-4, IL-5, IL-6 and/or IL-10 production.
Human gliomas provide an interesting example of tumor-associated immune dysfunction. The in vitro responses of T cells from patients who present with primary gliomas are impaired in their ability to respond in vitro to antigens and T cell nitrogens by proliferation and IL-2 production (Mahaley et al., 1977; Brooks et al., 1972; Elliott et al., 1984). Surgical removal of the primary tumor can result in restoration of systemic responses to T cell mitogens, which again decline with recurrence of the tumor (Brooks et al., 1981). Glioma patients also frequently fail to elicit delayed skin reactions (Brooks et al., 1972) and patients' T cells express reduced numbers of high affinity IL-2 receptors (Elliot et al., 1990a and Elliot et al., 1990b). It was recently reported that T cells from glioma patients exhibit defects in tyrosine phosphorylation of several proteins, reduced levels of PLCγ1 and p56kk, as well as reduced mobilization of calcium (Morford et al., 1997). Other studies demonstrated that cultures of glioblastoma cell lines produce one or more factors that inhibit antigen- and mitogen-stimulated proliferation and IL-2 production by T cells from healthy individuals (Rozman et al., 1987 and Elliot et al., 1992).